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CELLULAR PATHOLOGY > mechanisms of oncogenesis > Flashcards

mechanisms of oncogenesis Flashcards

1
Q

what are some lifestyle factors that are linked to cancer

A

smoking

obesity and weight

hormones

alcohol

sun and UV

lack of physical activity

poor diet

inherited genes

air pollution

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2
Q

Why is cancer defined as a disease of aging?

A

The older you get, the higher the risk of developing cancer

The longer we live the more time there is for DNA to accumulate mutations that may lead to cancer

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3
Q

What is cancer?

A

Disease of the loss of control of cell signalling pathway

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4
Q

Cancer is a group of diseases characterised by 4 distinct hallmarks. What are they?

A
  • Abnormal cell proliferation
  • Tumour formation
  • Invasion of neighbouring normal tissue
  • Metastasis to form new tumours at distant sites
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5
Q

What are carcinomas?

A

Cancers that occur in the epithelial cells

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6
Q

What are sarcomas?

A

Cancers that occur in the mesoderm cells (muscle and bone)

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7
Q

What are adenocarcinomas?

A

Cancers that occur in the glandular tissue

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8
Q

what are the 10 hallmarks of cancer

A
  • evading growth suppressors
  • avoiding immune destruction
  • enabling replicative immortality
  • tumour promoting inflammation
  • activating invasion and metastasis
  • inducing angiogenesis
  • genome instability and mutation
  • resisting cell death
  • deregulating cellular energetics
  • sustained proliferative signaling
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9
Q

what is meant by hallmarks of cancer

A

all the characteristics a normal cell has to undergo to become a tumour cell

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10
Q

what effect do carcinogens have on DNA

A

Carcinogens cause alterations to the DNA - mutation

DNA from tumours has been shown to contain many alterations from point mutations to deletions.

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11
Q

how does accumulation of DNA mutations occur and what does it result in

A

This accumulation occurs only after the cells defense mechanism of DNA repair have been evaded

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12
Q

what is germline mutation

A

Alteration in DNA (point mutations/deletion) within an egg or sperm cell is known as a germline mutation

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13
Q

can germline mutations be passed onto offspring

A

These mutations can be passed onto your offspring (it is an inheritable mutation)

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14
Q

how do germline mutations affect the risk of developing cancer

A

This does increase your risk of developing cancer BUT does not necessarily mean you will develop cancer immediately

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15
Q

how is germline mutation different to somatic mutation

A

germline mutation:
inheritable mutation

somatic mutation:
Cannot be passed on, found in daughter cells during cell division but it is NOT inheritable

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16
Q

describe the process of tumour formation from a single somatic cell

A

alteration in DNA of somatic cell

All cells in a primary tumour arise from a single cell: initiation of the
development of cancer is clonal

cell division of mutated cell = production of clonal cells = tumour formation

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17
Q

what do tumours that arise from somatic mutations do to help themselves survive

what is meant by sub clonal mutations?

A

It is the continued accumulation of mutations within the tumour (the tumour will continue to evolve and accumulate changes to help themselves survive)

clones that has arised from the same transformed cell but that have accumulated different mutations in them to help the tumour survive (this also explains the heterogeneity of cells in a tumour). this also explains why cells from the same tumour respond differently to treatment.

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18
Q

normal cells can receive signals to stimulate proliferation. What are 3 examples of these signals/

A
  • growth factors (PDGF, EGF)
  • cytokines (growth hormone, IL)
  • hormones (oestrogen)
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19
Q

in terms of proliferation and apoptosis, what is the balance between these in healthy cells?

A

proliferation = cell loss

HEALTHY CELLS

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20
Q

how do tumours arise from a normal cell

A

there are many genes involved in the regulation of the growth, apoptosis and differentiation of cell numbers

mutation in the genes that regulate these processes can lead to an imbalance between proliferation and cell loss

uncontrolled cell proliferation = tumour formation

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21
Q

what are the 2 categories of genes that regulate cell growth

A

oncogenes

tumour suppressor genes

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22
Q

what is the difference between oncogenes and proto-oncogenes

A

a proto oncogene codes for proteins responsible for cell proliferation

proto oncogene –> activated oncogene via mutation = leads to signals that cause uncontrolled growth
(tumour formation = cancer)

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23
Q

Role of tumour suppressor genes

A

Tumour suppressor genes inhibit both growth and tumour formation

They act as breaking signals during G1 phase of the cell cycle, to stop or slow the cell cycle before S phase (before DNA replication)

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24
Q

what happens if there is a mutation in the tumour suppressor gene

A

If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth (progression of cell cycle = tumor formation = cancer)

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25
Q

the formation of a tumour occurs as a result of changes to which 2 genes and what changes occur

A

This means the formation of a tumour as a result of:
1. mutation in proto-oncogene —> activated oncogene

  1. mutation in tumour suppressor gene
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26
Q

What are the 3 assumptions made for carcinogenesis models?

A
  1. Malignant transformation of a single cell is sufficient to give rise to a tumour
  2. Any cells in a tissue are equally likely to be transformed
  3. Once a malignant cell is generated the mean time to tumour detection is generally constant
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27
Q

What are the 5 models of cancer?

A

Model 1: mutational (genotoxic)

Model 2: genome instability

Model 3: non-genotoxic

Model 4: Darwinian(evolving tumour)

Model 5: tissue organisation

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28
Q

what are the 4 carcinogens categories

A

chemical

physical

heritable (predisposition)

viral

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29
Q

examples of chemical carcinogens

A

polycyclic aromatic hydrocarbons

aromatic amines

nitrosamines

alkylating agents

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30
Q

examples of physical carcinogens

A

radiation such as ionising and UV

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31
Q

examples of viral carcinogens

A

hepatitis B

Epstein Barr

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32
Q

What are the 4 major groups that exert their carcinogenic effects by adding functional groups to DNA bases called DNA adducts?

A
  1. Polycyclic aromatic hydrocarbons
  2. Aromatic amines
  3. Nitrosamines
  4. Alkylating agents
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33
Q

What is found in coal tar and how is this related to cancer?

A

Coal tar contains benzo(a)pyrene.

It enters cells VERY easily and when activated can become carcinogenic

34
Q

describe benzo(a)pyrene and how it is related to cancer

where is it commonly found - how does it get into our bodies?

A

Benzo(a)pyrene (BP) is a procarcinogen (NOT CARCINOGENIC)
When BP is taken into our bodies (via cigarette smoke) and is acted upon by microsomal enzymes, it is converted into Benzo(a)pyrene epoxide via addition of functional group.

This is when it becomes carcinogenic.

35
Q

What effect does Benzo(a)pyrene epoxide have on DNA?

A

IT IS A CARCINOGEN

Changes G—-> T in DNA

36
Q

What test can be carried out to find out if something is carcinogenic?

A

Ames Test

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria

mutation in bacteria = chemical is carcinogenic

37
Q

how does the Ames test work

A

You take rat liver extract (contains the microsomal enzymes), you mush it up and you combine it with a Salmonella strain that will only grow in the presence of histidine.

If you plate that onto an agar plate that lacks histidine, following overnight incubation, you should have very few colonies on that plate.
(If you get one or two, it’s due to natural reversion)

If you add the carcinogen being tested, and then plate it, and then you get lots of colonies, it suggest that there is now a change in the bacteria, and it can now grow in the absence of histidine. This confirms that the compound you’re testing is in fact carcinogenic.

38
Q

How do physical carcinogens act?

A

Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material

39
Q

Physical carcinogens include radiation. What 2 types can act as carcinogens?

A

ionising radiation
(x-ray, nuclear radiation)

UV radiation

40
Q

How does radiation act on DNA?

Is this reversible?

A

Radiation is a physical carcinogen
Radiation damages DNA by causing DNA breaks or pyrimidine dimers
These damages can be repaired BUT if not this leads to failed repair which leads to translocations and mutations

41
Q

Describe heritable carcinogens and the relation to cancer

A

An inherited germline mutation has an increased risk of developing certain tumours but are RARELY involved in CAUSING cancer immediately

42
Q

in hereditary malignant syndromes, what is the elevated cancer risk due to

A

In most hereditary malignant syndromes, the elevated cancer risk is due to a mutation of a single gene

(monogenic hereditary diseases)

43
Q

How could heritable carcinogens lead to an increase risk of cancer

A

most cases = mutation of a single gene

The affected genes usually have a controlling function on the cell cycle, apoptosis or the repair of DNA damage

A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer (predisposition for cancer)

44
Q

What are germline mutations?

can it be inherited

A

Present in egg or sperm
Can be inherited
Cause cancer family syndrome

45
Q

what are the 2 groups of syndrome predisposing to cancer

A

DNA repair defects

chromosomal abnormalities

46
Q

examples of DNA repair defects predisposing to cancer

A
  • Ataxia telangiectasia
  • Bloom’s syndrome
  • Fanconi’s anaemia
  • Li-Fraumeni syndrome
  • Lynch type II
  • Xeroderma pigmentosum
47
Q

examples of chromosomal abnormalities predisposing to cancer

A
  • Down’s syndrome

* Klinefelter’s syndrome

48
Q

What is Ataxia telangiectasia (‘spider veins’)?

mutation in what gene?

A
  • Neuromotor dysfunction
  • Dilation of blood vessels
  • Mutation in ATM gene
49
Q

what is the ATM gene

A

Codes for serine/threonine kinase (its function is to phosphorylate P53) that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis

50
Q

ATM gene codes for serine/threonine kinase.

What is the function of serine/threonine kinase

A

its function is to phosphorylate P53

51
Q

what can mutation in the ATM

A

mutation in gene = improper function in DNA repair etc

52
Q

What is Ataxia telangiectasia (‘spider veins’) a cancer predisposition for

A

Lymphoma
Leukaemia
Breast cancer

53
Q

blooms syndrome

what do people with this look like? (in terms of height)

what happens in this syndrome?

A

short stature (rarely exceed 5ft)

skin rash that develops after skin exposure

54
Q

what happens in Bloom syndrome

A

mutation of BLM gene

55
Q

what is the function of the BLM gene

A

Provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA

56
Q

what is Bloom syndrome a cancer predisposition for

A

Basal cell carcinoma

Squamous cell carcinoma

57
Q

What is Lynch type II?

A

Mutation in DNA mismatch repair genes (MMR genes):
MLH1

MSH2

MSH6

PMS2

58
Q

what is Lynch type II a cancer predisposition for

A

colorectal cancer

59
Q

sign of Lynch type II

A

NO SYMPTOMS

First sign that a person has Lynch type II is when symptoms of bowel and womb cancer develops

60
Q

Describe viruses as carcinogens

A

Most harm is caused when viruses multiply inside the infected cell, kill the cell (lysis) and release progeny to further infect other cells

In rare incidences it switches to a latent cycle

BUT

Some viruses can be tumorigenic (allow transformation of cells; tumour formation)

61
Q

What are some properties required of tumorigenic viruses? (3)

A

stable association with cells

must not kill cells

must evade immune surveillance of infected cells

62
Q

how do tumorigenic viruses form a stable association with cells

A
  • chromosomal integration

- episome(can replicate independently of chromosomal DNA)

63
Q

how do tumorigenic viruses ensure they do not kill host cells

A
  • non-permissive host (virus cannot replicate)
  • suppression of viral lytic cycle
  • viral release by budding
64
Q

how do tumorigenic viruses evade immune surveillance

A
  • immune suppression

- viral antigens not expressed at cell surface

65
Q

List some viruses that are associated with human cancer and the type of cancer they can result in

  1. DNA VIRUSES
  2. RNA VIRUSES
A

DNA VIRUSES
1. Epstein-Barr virus
• Burkitt’s lymphoma
• Nasopharyngeal carcinoma

  1. Papilloma virus
    • Cervical carcinoma
    • Warts
  2. Hepatitis B and C
    • Hepatoma

RNA RETROVIRUSES
• HTLV-I (Adult T-cell leukaemia, lymphoma)

66
Q

What is retinoblastoma?

A

A childhood cancer that affects the retina

67
Q

What causes retinoblastoma?

A

RB1 (the tumour suppressor gene) causes retinoblastoma when BOTH COPIES are mutated

68
Q

DESCRIBE Knudson’s hypothesis for hereditary cancers

A

Knudson found that there were 2 sets of patients:

  1. Patients presenting with the tumour at an early age
  2. Patients presenting with the tumour at a later age

He then found out this was because there are 2 types of retinoblastoma:

  1. The inherited form (as a result of a mutation in the Rb gene)
  2. The sporadic form

in the inherited form, the patients would have acquired the second mutations (and therefore both) at a much earlier age than the sporadic (non inherited) form.

In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis.

Stage at which they would have acquired BOTH mutations and therefore retinoblastoma?

inherited = earlier in life

sporadic = later in life

69
Q

describe the non genotoxic model of cancer

A

Non-genotoxic carcinogens have been shown to act as:

  • tumour promoters
  • endocrine-modifiers
  • receptor-mediators
  • immunosuppressants
  • inducers of tissue-specific toxicity and inflammatory responses
70
Q

example of non genotoxic carcinogen that acts as tumour promoters

A

1,4-dichlorobenzene

71
Q

example of non genotoxic carcinogen that acts as endocrine modifiers

A

17β-estradiol

72
Q

example of non genotoxic carcinogen that acts as receptor mediators

A

2,3,7,8-tetrachlorodibenzo-p-dioxin

73
Q

example of non genotoxic carcinogen that acts as immunosuppressants

A

cyclosporine

74
Q

example of non genotoxic carcinogen that acts as inducers of tissue-specific toxicity and inflammatory responses

A

metals such as arsenic and beryllium

75
Q

describe the darwinian model of carcinogens

A
  1. carcinogen exposure = normal cell accumulates mutations
  2. Natural selection
    This mutated cell will undergo changes to form a tumour (transformation)
  3. Tumour cells will be selected for ability to grow and invade
    (This tumour cell will also undergo artificial selection: when treating a patient with chemotherapy some tumour cells become resistant to the treatment = these tumour cells will therefore be able to expand and grow)

There can be the ODD mutation that is a disadvantage to the tumour cell (rare)

76
Q

Describe model 5: tissue organisation

Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research
What are they?

A
  1. Somatic mutation theory (SMT)

2. Tissue organisation field theory (TOFT)

77
Q

Describe the somatic mutation theory (SMT)

A

Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations.

Those mutations damage the genes which control cell proliferation and the cell cycle.

If these changes are not repaired = carcinogenesis

78
Q

Describe the tissue organization field theory (TOFT)

A

Carcinogenic agents destroy the normal tissue architecture, thus disrupting cell-to-cell signalling and compromising genomic integrity.

The DNA mutations are random and the effect of the tissue disruption, not the cause

79
Q

What is the immune system’s response to cancer?

does this get rid of the cancer?

A

The immune system will:

  • protect from virus-induced tumours
  • eliminate pathogens
  • identify and eliminate tumour cells

This leads to immune surveillance. However, despite this, tumours can still arise.

80
Q

What is cancer immunoediting?

A

ELIMINATION:
The immune system is able to eradicate developing tumours.

However some tumours are able to escape elimination and go onto equilibrium (cancer persistence)

EQUILIBRIUM (cancer persistence)
When incomplete removal is present, tumour cells remain dormant and enter equilibrium. The immune system exerts a potent and relentless pressure that contains the tumour. During this phase, some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase

ESCAPE (cancer progression)
The expanding tumour populations becomes clinically detectable.

81
Q

describe the mutational (genotoxic) model of cancer

A

Carcinogens can directly alter the structure of DNA (genotoxic), if this change in DNA is not repaired then it leads to an increased chance in developing a tumour.

The presence of multiple mutations in critical genes in a distinctive feature of cancer cells and supports that cancer arises through the accumulation of irreversible DNA damage

CELLULAR PATHOLOGY (10 decks)

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